Oxygen- and nitrogen-containing heterocycles, such as piperidine and tetrahydropyran rings, are widely distributed throughout natural products and are important scaffolds for many pharmaceutical compounds. Many modern medicinal agents contain chiral centers with only one enantiomer having desirable biological activity. Consequently, the development of methods for their asymmetric synthesis is of great importance. The Prins cyclization reaction has proven to be an extremely powerful method for the assembly of oxygen- and nitrogen-containing heterocycles. To date, stereoselective variants have relied on transferring chiral information from enantioenriched starting materials to the heterocyclic products. This proposal describes the development of an enantioselective Prins cyclization from achiral precursors, which will provide access to some previously elusive, synthetically valuable motifs. Since the enantiodetermining step of the Prins/aza-Prins cyclization proceeds via a charged oxocarbenium or iminium intermediate, traditional asymmetric Bronsted or Lewis acid catalysis is not a viable option. The proposed reaction aims to apply the novel concept of chiral counteranion-mediated asymmetric catalysis. Chiral, non-racemic thiourea catalysts have been shown to induce highly enantioselective transformations by binding to the counteranion of charged N-acyliminium and oxocarbenium species. Thiourea-catalyzed Prins and aza-Prins reactions providing tetrahydropyran and piperidine products will first be explored. Optimal reaction conditions as well as catalyst structure will be identified and the scope of the reaction will be surveyed. Variations of the Prins cyclization that have previously been developed will be explored for the enantioselective synthesis of a wide array of heterocyclic scaffolds with handles for further synthetic elaboration. Extension of the Prins cyclization strategy to the asymmetric synthesis of tetrahydrofurans and pyrrolidines will also be investigated. Since thiourea-anion binding asymmetric catalysis is in its infancy, the development of these reactions will further define the generality of this strategy. PUBLIC HEALTH RELEVANCE: Because the two enantiomers of a pharmaceutical substance can possess widely different biological activities, the development of methods for the synthesis of chiral drugs in enantiomerically pure form is critical for public health. This application describes an efficient and general method for the asymmetric synthesis of heterocycles that are commonly found in biologically active molecules.